PROJECT SUMMARY/ABSTRACT UTIs are a common source of patient morbidity that can result in permanent renal damage. Historically, antibiotics have been the standard in UTI treatment and routinely used for prevention. However, the emergence of multidrug resistant uropathogens limits the long-term viability of antimicrobial strategies based solely on antibiotic therapy. As a result, alternative methods for UTI treatment and prevention are needed. The lining of the urinary tract, or urothelium, serves essential roles in the detection and elimination of invading bacteria, including production of cytokines and antimicrobial peptides (AMPs). These intrinsic qualities of innate defense within the urothelium might be harnessed therapeutically to prevent and treat UTI. A fundamental knowledge gap exists, however, in our understanding of how these different factors contribute to limiting UTI susceptibility. The objective of this research project is to define the mechanisms by which the bladder urothelium defends the urinary tract from invading uropathogenic bacteria. This proposal tests the hypothesis that the cytokine interleukin-6 (IL-6) promotes clearance of uropathogenic Escherichia coli through activation of the Signal transducer and activator of transcription 3 (Stat3) transcription factor and AMP production. The anticipated outcome of this research is to establish the contributions of the IL-6/Stat3/AMP signal transduction cascade to the host defense properties of the urothelium. Aim 1 will investigate how IL-6 directly limits urothelial susceptibility to UTI. Aim 2 will establish the roles for urothelial Stat3 during UTI. Aim 3 will explore the impact of AMPs in preventing UTI. Together, these Aims look to implicate the IL-6/Stat3/AMP pathway as a key driver of urothelial susceptibility to UTI and thus as a potential target of UTI treatment. The completion of this award will combine structured career development activities and mentored research programs to enable the transition from a junior investigator to an independently funded surgeon-scientist.